Project description
Conserved non-coding elements: regulatory genome evolution
Although nearly 99 % of the human genome is non-coding, it is biologically active and essential to fundamental processes. Conserved non-coding elements (CNEs) are DNA sequences that can be conserved within species for up to hundreds of years. How they evolve at a functional level and why they are so conserved is unknown. With the support of the Marie Skłodowska-Curie Actions programme, the ENCORE project aims to address this knowledge gap, hypothesising that CNEs are ancient transcription-factor-binding hubs that act as dynamic multi-genic regulators to which new gene targets can be added or removed during evolution. They will develop maps of conserved, gained and lost interactions in different species and test their functional impact.
Objective
Thousands of Conserved Non-coding Elements (CNEs) are shared by jawed vertebrates, some of which were shown to be important developmental enhancers. However, how these intriguing elements evolve at the functional level and why they are so conserved in sequence remain some of the biggest mysteries in the field of regulatory genomics. In this project, I build a novel view of CNE function and evolution based on my preliminary data and recent breakthroughs on enhancer pleiotropy. This working hypothesis posits that CNEs are ancient transcription factor binding hubs that act as dynamic multi-genic regulators to which new gene targets can be added/removed during evolution. Taking advantage of the exceptional conservation of CNEs, I propose the experimental framework to test this hypothesis on orthologous elements across major vertebrate clades using cutting-edge methodology combining Capture-HiC, RNA-seq and ATAC-seq in shark, chicken and mouse. This approach will provide comparative CNE-target contact maps that will reveal conserved as well as gained and lost interactions in each species, whose functional impact will be tested using CRISPR knockout and interference in mouse neuronal differentiation. In summary, this project will address long-standing questions on the evolution of the regulatory genome and offer insights into the flexibility of enhancers to acquire and lose targets in evolution, expanding our understanding on the pervasiveness and evolution of regulatory pleiotropy.
Fields of science
Keywords
Programme(s)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Funding Scheme
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsCoordinator
08003 Barcelona
Spain